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Audrey Burke (Halle Berry) and her warm and loving husband Brian (David Duchovny) have been happily married 11 years; they have a 10-year-old daughter named Harper (Alexis Llewellyn) and a 6-year-old son named Dory (Micah Berry). Jerry Sunborne (Benicio del Toro) is a heroin addict who has been Brian’s close friend since childhood.

Audrey gets tragic news delivered to her door by the local police: Brian has been killed in an attempt to defend a woman who was being beaten by her husband. On the day of the funeral Audrey realizes that she has forgotten to inform Jerry of Brian's death. Her brother Neal (Omar Benson Miller) delivers the message to Jerry and takes him to the funeral.

Audrey invites Jerry to move into the room adjacent to their garage, which he does. During his stay at the Burke home Jerry struggles to remain drug-free and also becomes very fond of Harper and Dory. The relationship between Jerry and Audrey is fragile and complicated. Jerry helps Audrey cope in many ways, including lying with her in bed to help her sleep. But Audrey, upset and confused, takes out her grief at Brian's death on Jerry. She becomes angry when Jerry helps Dory overcome his fear of submerging his head in the pool, as this had been something Brian had tried to do for years. Eventually her rudeness to him causes Jerry to move out and relapse with heroin. Audrey and Neal rescue and rehabilitate him and he agrees to admit himself to a specialized clinic. At first Harper, who has come to love Jerry, is angry that he is leaving, but after he leaves her a heartfelt note she forgives him. At the close of the film Jerry is still struggling with his addiction but seems to be well on his way to recovery. He leaves flowers on Audrey's doorstep with a note that reads, "Accept the good."

The film was released October 19, 2007 in 1,142 theaters in the United States and Canada and grossed $1.5 million its opening weekend, ranking #15 at the box office.[4] As of November 18, 2007, it has grossed $3,287,315.

Critics gave the film generally favorable reviews. As of January 29, 2008 on the review aggregator Rotten Tomatoes, 64% of critics gave the film positive reviews, based on 117 reviews.[5] On Metacritic, the film had an average score of 63 out of 100, based on 30 reviews.[6]

Josh Rosenblatt of The Austin Chronicle gave the film 4 stars and said the film is "an impeccably constructed and perfectly paced drama of domestic and internal volatility." Rosenblatt wrote "Berry is brilliant here, as good as she’s ever been" and said of Benicio del Toro's performance, "with Things We Lost in the Fire, he's managed to top even himself."[7] Jack Mathews of the New York Daily News gave the film 3½ stars and called it "an award contender...in several positions." Mathews said it is "beautifully written" by Allan Loeb and "acted with heartbreaking efficiency by Halle Berry and Benicio del Toro."[8]Los Angeles Daily News critic Glenn Whipp said the film "will probably be most American moviegoers' introduction to the Dogma-flavored direction of Susanne Bier" and said "Newcomers probably won't be as irritated by Bier's herky-jerky, hand-held camerawork, desaturated colors and odd obsession with random close-ups, especially of characters' eyes...For the rest of us, Bier's directorial tics are beginning to wear thin..."[9]

Claudia Puig of USA Today gave the film 3 stars out of 4 and said "The movie makes some missteps, most of them in pacing and length, and the story veers occasionally into melodrama, but it is saved by the powerful performance of Benicio del Toro", calling him "hypnotically watchable."[10] Joe Morgenstern of The Wall Street Journal wrote "Flawed as it is, the movie as a whole is a guilty pleasure." Morgenstern said "del Toro is a fearless actor" and said the film "would be fairly lifeless without him." Morgenstern wrote "Berry is skillful and affecting, occasionally ferocious, and subtle enough for two, in what is essentially a two-character drama."[11] Stephen Holden of The New York Times said the film "is the kind of awards-seeking Hollywood movie that bends over backward to prove that serious American movies can hold their own with the best films from overseas. They don’t, of course, except in very rare instances."[12]Kyle Smith of the New York Post gave the film 1½ stars out of 4 and said the film "was made to win awards, and I'm here to present it with one: the Cliché of the Year honors, otherwise known as the Hackney.[13]